Medical Students 
Graduate Medical Education 
Pharmacokinetics: What the body does to drugs
Drug Absorption
- Definition = the rate at which a drug leaves its site of administration
- o lipid or water solubility determines absorption and elimination characteristics of drugs
- o drugs can cross membranes by three mechanisms
1) simple diffusion (proportional to diffusion gradient)
-Mechanism used by highly lipid soluble, small molecular weight drugs
2) facilitated transport (passive) - large molecular weight drugs
3) energy-dependent transport - large molecular weight, lipid insoluble drugs generally
- Factors affecting absorption
- o lipid solubility - highly lipid soluble drugs easily pass through cell membranes
- o concentration of drug - a higher concentration = increased absorption
- o Blood supply - well perfused area will absorb drug faster
- o Vascular tone - vasodilation favors absorption (as opposed to a clinical situation such as shock, where absorption is generally poor)
- o degree of ionization (nonionized drugs tend to be more lipid soluble)
Drug Distribution
- Distribution, or movement of a drug through different bodily compartments, depends upon:
- o degree of ionization (which is influenced by a drug's pKa and the surrounding pH)
- o protein binding
- § unbound (free) form is active
- § Usually, acidic drugs bind to albumin, basic drugs to a1-acid glycoprotein
- § bound drug may act as a reservoir
- o Molecular weight (smaller drugs distribute more quickly)
- o lipid solubility (independent of ionization)
- Why do IV anesthetics typically have such a rapid onset and offset? DISTRIBUTION!
- o Highly perfused tissues (i.e. brain) receive approximately 75% of total CO - while only accounting for 10% of total body mass
- o Thus, CNS active drugs with high lipid solubility (most IV anesthetics) rapidly reach their target site, and cause rapid onset
- o BUT, lipid solubility is the two-edged sword - it allows the drugs to reach the effect site quickly (onset), but it also causes them to quickly redistribute to inactive sites (lean body mass), thus terminating the action of the drug
- o Be Warned! The above discussion only applies to single bolus administration. Multiple doses or continuous IV administration results in saturation of the inactive sites, which can then act as drug reservoirs. This effect will prolong termination of action after discontinuation of prolonged administration.
- o After saturation of inactive sites has occurred, termination of action tends to depend upon elimination to decrease plasma drug concentration rather than redistribution
Drug Metabolism
- Occurs mainly in the liver, but also in the lungs, kidneys and GI tract
- Converts drugs into water-soluble metabolites (often, but not always inactive) so that they may be excreted - lipid soluble drugs are easily reabsorbed in the renal tubules and thus not excreted
- Cytochrome P450 system is largely responsible for the metabolism of these drugs
- Divided into phase I and phase II reactions
- o Phase I - oxidation, reduction, and hydrolysis - makes drugs more water-soluble by introducing polar groups (i.e. hydroxyl)
- o Phase II - conjugation - couples the drug to glucuronate, acetate, or an amino acid so that the drug may be excreted
Drug Excretion
- Drugs are excreted as metabolites or unchanged (water-soluble drugs more frequently unchanged, as they cannot be reabsorbed by renal tubular cells)
- Primary site of excretion are the kidney, but can be the lungs, skin, bile, breast milk, saliva, and sweat.
- Kidneys excrete drugs by:
- o passive glomerular filtration
- o active tubular secretion
- o passive diffusion
